Series of 4-substituted-2-(5-nitro-2-furyl) quinazolines



United States Patent 3,324,122 SERIES OF 4-SUBSTITUTED-2-(5-NITRO-2-FURYL) QUINAZOLINES Homer A. Burch, Norwich, N.Y., assignor to The Norwich Pharmacal Company, a corporation of New York No Drawing. Filed Dec. 14, 1964, Ser. No. 418,311 8 Claims. (Cl. 260-2475) This invention relates to a new series of chemical compounds. More particularly, it is concerned with a closely related series of 4-substituted-2-(5-nitro-2-furyl)quin-azolines of the formula:

wherein X represents in which R is selected from the group consisting of hydrogen, lower alkyl, hydroxy (lower) alkyl, lower alkoxyalkyl and amino; and R is selected from the group consisting of hydroxy (lower) alkyl, lower alkoxyalkyl and morpholinopropyl. This invention is also concerned with the preparation of such compounds.

The compounds of this invention bearing the group, in which R and R have the significance above related, in the 4-position are particularly distinguished by their ability to inhibit the growth of microorganisms. Representative of the very high order of antimicrobial activity resident in the members of this series is the effect elicited by the compound 4-[ bis-(2 hydroxyethyl)amino] 2-(5-nitro-2-furyl)quinazoline against a broad spectrum of gram-positive and gram-negative organisms under the commonly employed serial dilution technique:

Minimum inhibiting Microorganism concentration in ,ug./1'1ll. Escherichia coli 0.12 Staphylococcus aureus 0.38 Salmonella typhosa 0.048

Pseudomonas aeruginosa 3.0 Proteus vulgarz's 6.0 Streptococcus pyogenes 0.024 Streptococcus agtzlactiae 0.19 Erysl'pelothrix insidiosa 0.012 Aerobacter aerogenes 3.0

Thus, these compounds are adapted to be combined with suitable carriers in the form of dusts, suspensions, ointment, sprays and the like to provide compositions designed to prevent and eradicate bacterial contamination.

The compounds of this invent-ion having the substituent are also capable of suppressing systemic infection in animals provoked by Staphylococcus aureus. When administered perorally in a dose of from 50-200 mgL/kg. to mice lethally infected with that bacterium, protect-ion against mortality is secured.

3,324,122 Patented June 6, 1967 in which R and R have the aforeassigned significance.

In carrying out the reaction it is preferred to bring together the reactants in the presence of a solvent such as di-methylformamide and supply heatto the reaction mixture to 'hasten its progress. When the reaction is complete an inert solvent in which the desired end product has low solubility, such as water or petroleum ether, is conveniently added to the mixture to evoke the separation of solid material, which is secured by filtration and purified, if necessary or desirable, to yield the desired end product.

In order that this invention may be readily available to and understood 'by those skilled in the art, the following examples are supplied:

EXAMPLE I A. 2-(5-nirro-2-furyl) -4(3H) -quinaz0lin0ne (NF-732) o-Aminobenza-mide (6.8 g. or 0.05 mole) is dissolved in 30 cc. dimethylformamide and any insoluble material filtered off. To the solution 5.0 g. (0.05 mole) of calcium carbonate is added. While stirring 8.75 g. (0.05 mole) of S-nitrofuroylchloride in 20 cc. dimethylf-ormamide is added. The mixture is heated on a hot plate for one hour. The insoluble material which consists of calcium chloride and unreact-ed calcium carbonate is filtered off. The filtrate upon cooling gives 3.9 g. (yield 30%) of product. It may be recrystallized from cc. dimethylfor-mamide.

Analysis.Calcd. for C12H7N304Z C, 56.03; H, 2.74; N, 16.34. Found: C, 55.90; H, 3.00; 'N, 16.31.

B. 4-chloro-2-'(5-nitr0-2-furyl)quinazoline (NF-1039) A 5 1., three neck flask, fitted with stirrer, thermometer and condenser, is charged with 159 g. (0.766 mole) of phosphorus pentachloride and 790 ml. of phosphorus oxychloride. To the stirred mixture is added 198 g. (0.77 mole) of the compound of A. above in small portions at room temperature. The mixture is refluxed for 1 hr. The mixture is cooled to room temperature, diluted with ca. 3 l. of petroleum ether, chilled thoroughly and filtered. The prodnot (208 g.) is purified by Soxhlet extraction with toluene. The toluene solution is chilled and filtered. The product is obtained as long, yellow needles melting at 196.5-198.5 in ayield of 106 g.

Analysis.-Calcd. for C H ClN O C, 52.28; H, 2.19; Cl, 12.86. Found: C, 52.38; H, 2.14; CI, 12.79.

EXAMPLE II 4- [Z-lzydroxyethyl(Z-hydro-xy propyl) amino] -2- (S-nirro- Z-fmyl) quinazoline (NF-1174) A 1 1., three-neck flask, fitted with a stirrer, is charged with 30 g. (0.11 mole) of the compound of Example I, B., and 26.5 g. (0.221 mole) of isopropanolethanolamine in 750 ml. of dimethylformamide. The solution is heated on a steam bath for 1 hour. The solution is diluted with water until a solid begins to separate. The mixture is cooled; the product is collected by filtration, and recrystallized from isopropyl alcohol (Darco). The product separates as yellow platelets melting at l65166 (corr.), in ayield of 18 g. (46% Analysis.Calcd. for C H N O C, 56.98; H, 5.06; N, 15.64. Found: C, 57.14; H, 5.25; N, 15.65.

EXAMPLE III 4-b1's(2-hydr0xypr0pyl)amino-2-(5-nitr0-2-furyl) quinazoline (NF-1144) A 1 l., three-neck flask, fitted with a stirrer, is charged with 40 g. (0.145 mole) of the compound of Example I, B., and 40 g. (0.3 mole) of 1,1-iminodi-2-propanol in 500 ml. of dimethylformamide. The solution is heated on a steam bath for 2 hours. The solution is diluted with water until a solid begins to separate. The mixture is cooled; the crude product is collected by filtration, and recrystallized from isopropyl alcohol. The product separates as yellow needles melting at 169170 (corr.) in a yield of 39 g. (73%).

Analysis.Calcd. for C H 'N O C, 58.06; H, 5.41; N, 15.05. Found: C, 57.94; H, 5.55; N, 14.81.

EXAMPLE IV 4-butyl (Z-hydroxyethyl amino-Z- 5 -nitr-2-furyl quinazoline (NF-1142 A 1 l., three-neck flask, fitted With a stirrer, was charged with 40 g. (0.145 mole) of the compound of Example I, B., and 36 g. (0.3 mole) of N butylethanol-amine in 500 ml. of dimethylformamide. The solution is heated on a steam bath, with stirring, for 2 hours. The solution is diluted with water until a solid begins to separate. The mixture is cooled; the yellow solid was collected by filtration, and recrystallized from isopropyl alcohol. The product is collected as yellow needles melting at 120121 (corr.) in a yield of 39 g. (75% Analysis.C-alcd. for C H N O C, H, N, 15.72. Found: C, 60.76; H, 5.76; N, 15.76.

EXAMPLE V 4 -bis- 2 -hydroxyethyl amino-2 5 -n itro-Z-fruyl quinazoline (NF -1 088) A 500 ml., three-neck flask, fitted with a stirrer, was charged with 30.2 g. (0.11 mole) of the compound of Example I, B., and 26.3 g. (0.25 mole) of diethanolamine in 300 ml. of dimethylformamide. The solution is heated on a steam bath for 2 hours. The solution is diluted with water until a solid begins to separate. The mixture is cooled and the crude product is collected by filtration and recrystallized from ethanol. The product separates as yellow platelets melting at 162.5164.5 (corr.) in a yield of 22 g. (58%).

Further recrystallization from ethanol gives a yellow solid melting at 167-168 (corr.).

AnaIysis.Calcd. for C1 H1 N405i C, H, N, 16.27. Found: C, 55.90; H, 47.5; N, 16.36.

EXAMPLE VI 4 2 -hydr0xyethyl methylam in0-2- 5 -nitr0-2-furyl quinazoline (NF-1081 A mixture of 50 g. (0.182 mole) of the compound of Example I, B., and 34 g. (0.45 mole) of N-methylethanol- EXAMPLE VII 4-(Zanethoxyethyl)amino-2-(5-nitro-2-fulyl) quinazoline (NF-1175) A 2 1., three-neck flask, fitted with a stirrer, condenser, and a stopper, is charged with 40 g. (0.145 mole) of the compound of Example I, B., and 22.5 g. (0.3 mole) of Z-methoxyethylamine in 1 l. of benzene. The mixture is refluxed for 1 hour. The cooled mixture is diluted with petroleum ether. The crude product is collected by filtration, and recrystallized from methyl alcohol. The product separates as yellow needles melting at -157 in a yield of 26 g. (57% Further recrystallizations from methyl alcohol raises the melting point to 162 (corr.).

Analysis.-Calcd. for C H N O C, 57.32; H, 4.49; N, 17.83. Found: C, 57.30; H, 4.61; N, 17.74.

EXAMPLE VIII 4-(3-methoxypropylamino)2-(5-nitr0-2-furyl) quinazoline (NF-1145) A 1 1., three-neck flask, fitted with a stirrer, is charged with 35 g. (0.127 mole) of the compound of Example I, B., and 23.1 g. (0.26 mole) of methoxypropylamine in 500 ml. of dimethylformamide. The solution is heated on a steam bath for 2 hours. The solution is diluted with Water until a solid begins to separate. The mixture is cooled; the crude product is collected by filtration, and recrystallized from isopropyl alcohol. The product separates as yellow platelets melting at 143-145 (corr.) in a yield of 33 g. (82%).

Analysis.Calcd. for C H N O C, 58.53; H, 4.91; N, 17.07. Found: C, 58.68;H, 4.80; N, 16.87.

EXAMPLE IX 4 -bis( Z-ethoxyethyl am ino-Z 5 -nitr0-2 -fwyl quinazoline (NF-1127) A 2 l., three-neck flask, fitted with a stirrer, is charged with 35 g. (0.127 mole) of the compound of Example I, B., and 42 g. (0.26 mole) of diethoxyethylamine in 1 l. of dimethylformamide. The solution is heated on a steam bath, with stirring, for 2 hours. The solution is diluted with water until a solid begins to separate. The mixture is cooled; the crude product is collected by filtration, and recrystallized from isopropyl alcohol. The product separates as yellow needles melting at 6061 (corr.) in a yield of 40 g. (79%).

Analysis.-Calcd. for C H N O C, 59.99; H, 6.04; N, 13.99. Found: C, 60.03; H, 5.85; N, 14.13.

EXAMPLE X 4-(2-hydr0xyethyl amino-Z- (5 -nitr0-2-furyl quinazoline (NF-1099) A solution of the compound of Example I, B. (30.2 g., 0.11 mole) and 15 g. (0.25 mole) of Z-ethanolamine in 800 ml. of dimethylformamide is heated on a steam bath for 2 hours. The solution is diluted with water until a solid begins to separate. The mixture is cooled and filtered to give a bright yellow solid. Recrystallization from ethanol gives the product in a yield of 31 g. (94%) (M.P. 221-223 Analysis.-Calcd. for C H N O C, 56.00; H, 4.03; N, 18.66. Found: C, 56.05; H, 4.41; N, 18.48.

. 5 EXAMPLE XI 4 [3- 4-m0f1'2h0lin0 propyl amino-Z- (5 -nitro-2-fwryl quinazoline dihydrochloride (NF-1100) A 2 l., three-neck flask, fitted with a stirrer, a condenser and a stopper is charged with 30.2 g. (0.11 mole) of the compound of Example I, B., and 36 g. (0.25 mole) of 3-aminopropylmorph-oline in 750 ml. of benzene. and is refluxed for 1.5 hours. The mixture is cooled and diluted with petroleum ether. A yellow solid is collected by filtration, slurried in.cold water and made basic with sodium hydroxide solution. The free base, melting at 164-166, is collected by filtration in a yield of 42 g. (100%). Recrystallization from ethanol gives the product as yellow platelets melting at 170-1715 (corn).

Analysis.Calcd. for C H N O C, 59.52; H, 5.52; N, 18.27. Found: C, 59.69; H, 5.50; N, 18.28.

The free base (40 g., 0.104 mole) is dissolved in 500 ml. of glacial acetic acid and anhydrous hydrogen chloride is bubbled into the solution until saturated. The mixture is cooled and diluted with anhydrous ether. A yellow solid is collected by filtration and recrystallized from ethanot to give the hydrochloride as a yellow solid melting at 211213 in a yield of 30 g. (63.5%).

Analysis.Calcd. for C H N O 2HCl: C, 50.00; H, 5.08; Cl. 15.34. Found: C, 50.07; H, 5.02; Cl, 15.07.

EXAMPLE XII 4-( 3-hydroxypropylamino) -2- 5 -nitr-2-furyl quinazoline (NF-1220) A 1 1., three-neck flask fitted with a stirrer is charged with 35 g. (0.127 mole) of the compound of Example I, B., and 19.5 g. (0.26 mole) of S-aminopropanol in 500 ml. of dimethylformamide. The mixture is heated on a steam bath with stirring for 1 hour. The solution is diluted with water and cooled. The brown product is collected by filtration and recrystallized from acetonitrile. The product separates as yellow platelets melting at 180- 183 (corr.) in ayield of 22 g. (55% Analysis.Calcd. for C H N O C, 57.32; H, 4.49; N, 17.83. Found: C, 57.55; H, 4.50; N, 17.81.

EXAMPLE XIII 4-[1-(2-hydr0xyethyl)hydrazino]-2-(5-nitro-2-furyl) quinazoline (NF-1193) A 1 1., three-neck flask, fitted with a stirrer is charged with 40 g. (0.145 mole) of the compound of Example I, B., and 28.5 g. (22.8 g., 0.3 mole) of 80% hydroxyethylhydrazine in 500 ml. of dimethylformamide. The mixture is allowed to stand for 15 minutes. The temperature approaches 40. The solution is then heated to 60. The solution is diluted with water and the mixture is cooled. The solid is collected by filtration to yield 43 g. (94%); 34 g. of this product is recrystallized from nitromethane to yield yellow needles melting at 186-188 (corn) in a yield of 28 g.

Further recrystallization from nitromethane raises the melting point to 190-191 (corn).

Analysis.Calcd. for C H N O C, 53.33; H, 4.16; N, 22.22. Found: C, 53.53; H, 4.29; N, 22.43.

EXAMPLE XIV 4-[ (Z-hydroxyethyl) isopropylamino] -2-(5-nitr0-2-furyl) quinazoline (NF-1192 A 1 l., three-neck flask, fitted with a stirrer is charged with 35 g. (0.127 mole) of the compound of Example I, B., and 25 g. (0.242 mole) of N-isopropylethanolamine in 500 ml. of dimethylformamide. The solution is heated on a steam bath for 2 hours. The solution is diluted with water until a solid separates and the mixture is cooled. The product is collected by filtration and recrystallized from isopropyl alcohol. The product separates as yellow platelets melting at l48150 in a yield of 21 g. (48%).

Further recrystallization from isopropyl alcohol raises the melting point to 157-158 (corn) Analysis.Calcd. for CHI-113N404: C, 59.64; H, 5.30; N, 16.37. Found: C, 59.70; H, 5.38; N, 16.50.

What is claimed is:

1. A compound of the formula:

wherein X is 3. The compound of the formula NHCHQCHaOH 4. The compound of the formula:

/cH2cH,oH N

oH omcHooH 5. The compound of the formula:

(oHmoH OH2CH2OH 6. The compound of the formula;

NHCHZCHZOCHE 7 7. The compound of the formula:

CIIQCH! NIICHzCHziCHzN I II CHzCHq I N 0 CH ONL JA J JH N c H 8. The compound of the formula:

HENRY R. JILES, Examiner.

JOSEPH A. NARCAVAGE, Assislant Examiner. 15 

1. A COMPOUND OF THE FORMULA: 